Racial/ethnic differences in smoking are well documented; African Americans smoke fewer cigarettes per day than Whites but experience disproportionately greater smoking attributable morbidity and mortality. Well documented disparities also exist in smoking cessation with African Americans consistently quitting at lower rates than Whites. However, to-date, no adequately powered study, stratified on race, has been conducted to confirm this finding using a rigorous study design or to understand the mechanisms accounting for differential quit rates in African Americans relative to Whites. The objectives of this application are to 1) describe the differences in smoking cessation among AA and White smokers treated with varenicline, 2) identify the smoking, psychosocial, treatment process, and biological factors that independently explain the relationship between race/ethnicity and cotinine-verified 7-day abstinence in African American and White smokers, and 3) examine the side effect profile of varenicline by smoking level. These aims will be accomplished through a prospective cohort intervention study, stratified on race, age (< 40, > 40), and gender among 448 participants (224 African American, 224 White). All participants will receive 3 months of varenicline, the most effective of currently available smoking cessation medications, standard educational materials, and six sessions of smoking cessation counseling. This study is innovative. It will be the first known study to report on the use of varenicline in As, the first to examine varenicline in light smokers (<10 cpd) and among a wide range of smoking levels (3-20 cpd), the first head-to-head study, stratified on race, designed to prospectively compare pharmacotherapy in AAs versus Whites, and one of a few to explore mechanisms underlying disparities in quitting between AA and White smokers. The impact of these findings will be considerable, having ramifications for treatment, clinical practice, and policy. Significan knowledge will be gained about African American-White differences in quitting. Findings have the potential to improve tobacco use treatment by moving the field away from a generic focus on race/ethnicity toward a targeted focus on modifiable smoking, psychosocial, and treatment process factors most relevant to African Americans and to Whites. PUBLIC HEALTH RELEVANCE: African Americans smoking fewer cigarettes per day and experience greater smoking-related disease and death, yet consistently quit smoking at lower rates than Whites. Little is known about the reasons for this disparity. This study will examine mechanisms explaining lower quit rates in African Americans relative to Whites and has the potential to significantly improve tobacco use treatment outcomes by identifying specific barriers and facilitators to quitting smoking for African Americans and for Whites.